Genomic and genetic analysis of liver and kidney toxicity of trichloroethylene

The need to account for genetic differences among humans in cancer susceptibility and risk assessment is becoming ever more evident to both the scientific community and regulatory agencies. Dr. Rusyn’s lab uses Trichloroethylene (TCE), a man-made, industrial chemical that has become one of the nation’s most prevalent groundwater pollutants, as a model environmental contaminant that individuals may respond to differently after exposure, but for which genetic factors are not being fully considered in risk assessment.

Project 2

Dr. Rusyn and his team are working to elucidate the genetic controls underlying species- and organ-specific metabolism and toxicity of TCE.

Ivan Rusyn, PhD

Professor

Previous research from Dr. Rusyn’s lab established that the genetic makeup of the host plays a key role in metabolism of TCE and its biological effects in mouse liver. Using genetically diverse inbred mouse strains, his team will assess inter-individual differences in TCE metabolism by collecting time course, dose-response, and repeat dose data on TCE metabolites in blood and tissues. These data will be used to investigate the genetic causes of variation in the metabolism of TCE, a step crucial for understanding the potential for TCE-induced adverse health effects in a heterogeneous human population.

Dr. Rusyn will also dissect the complex mechanisms of action of an environmental agent by constructing a population-wide physiologically based pharmacokinetic (PBPK) model for TCE metabolism, which will account for inter-individual variability in metabolism from the genetics point of view by using the time-course and dose-response data obtained from the genetically-diverse mice. His team will determine the effects of inter-individual genetic variability on strain-specific responses to TCE through dose-response modeling of gene expression and metabolomics data. Collectively, this project is timely in proposing a paradigm that will not only offer valuable insights into the molecular basis for genetically-determined variability in response to TCE, but also will provide necessary science-based underpinnings and tools for the new paradigms being incorporated into the risk assessment and decision-making on TCE and related chlorinated solvents, as well as other environmental agents.